Recombinant Adenovirus-Mediated HIF-l[alpha] Ameliorates Neurological Dysfunction by Improving Energy Metabolism in Ischemic Penumbra After Cerebral Ischemia-Reperfusion in Rats

Background: Hypoxia inducible factor-la (HIF-1[alpha]) regulates glucose metabolism during ischemia. This study investigated the effect of recombinant adenovirus HIF-1[alpha] on neurological function and energy metabolism in a rat cerebral ischemia-reperfusion model. Methods: Rats were divided into four groups: sham-operated (Sham) group, cerebral ischemia-reperfusion (CIR) group, recombinant adenovirus empty vector (Ad) group, and recombinant adenovirus-mediated HIF-1[alpha] (AdHIF-l[alpha]) group. The AdHTF-la group and the Ad group were injected with AdHIF-1[alpha] and Ad in the lateral ventricle. The mNSS was performed at post-ischemia day 0 (P0) and P1, P14 and P28. At P14, the cerebral infarct volume was compared. At P28, HE staining, Nissl stains and TUNEL staining were performed. The expression of HIF-1[alpha], GLUT1 and PFKFB3 were evaluated by Western Blot and immunohistochemistry. High performance liquid chromatography (HPLC) was used to determine the expression of GLUT1 and PFKFB3, and the level of energy metabolites: ATP, ADP and AMP. Results: mNSS scores in the AdHIF-l[alpha] group were consistently lower than those in the CIR and Ad groups from P14 (P < 0.05) and Ad groups (P < 0.05). The cerebral infarct volume was reduced in the AdHIF-1[alpha] group compared with that in CIR group and Ad group (P < 0.05). At P28, HE showed better pathological changes in AdHIF-1[alpha] group. The number of Nissl bodies was increased in the AdHIF-1[alpha] group compared with the CIR and Ad groups (P < 0.05). The number of apoptotic cells in the AdHIF-1[alpha] group was fewer than that in the CIR and Ad groups (P< 0.05). The expression of HIF-l[alpha], GLUT1 and PFKFB3 was significantly higher in the AdHIF-l[alpha] group compared with the CIR and Ad groups (P < 0.05). The ATP, ADP and AMP in the ischemic penumbra were also higher in the AdHIF-1[alpha] group (P < 0.05). Conclusion: HIF-1[alpha] promoted neurological function recovery and decreased cerebral infarct volume in rats after cerebral ischemia-reperfusion injury by improving energy metabolism. Keywords: cerebral ischemia-reperfusion injury, HIF-l[alpha], energy metabolism, glucose transporter protein-1, GLUT1, 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3, PFKFB3